Core 3 will design, implement and review all clinical trials sponsored by the SPORE application. There are four major areas of therapeutic intervention to be evaluated by clinical trials overseen by the core. First, therapeutics to overcome chemoresistance will be evaluated. UG-BG, a potent inhibitor of 06-alkylguanine- DNA alkyltransferase (AGT), the major mediator of chemoresistance among malignant gliomas, is ineffective and associated with significant toxicity when administered systemically. Therefore we will evaluate the compartmental administration of Ub-BG, as well as other agents identified in Project 4, via intrathecal injection for patients with neoplastic meningitis (NM) and intratumorally via intracerebral microinfusion (ICM) for patients with malignant brain tumors. Second, we will continue to evaluate therapeutics targeting tumor- specific markers (Project l), including armed and unarmed monoclonal antibodies (MAbs) and recombinant immunotoxins, delivered compartmentally via injection into the resection cavity or into the intrathecal space, or via direct intratumoral microinfusion. Therapeutic targets for these agents include EGFR, EGFRvIII, tenascin C, GP 240, MDRP3, GPNMB as well as others identified in Project 2. Our recent Phase I1 study showed that I-labeled anti-tenascin MAb 81C6 significantly improved survival for patients with newly diagnosed malignant glioma compared to conventional external beam radiotherapy and chemotherapy. Therefore, we are advancing our extensive preclinical and clinical studies with "'1-81 C6 and investigating the role of human and mouse chimeric MAbs, MAb fragments such as F(ab'), and alternative radioisotopes such as astatine- 211. The third major area of focus is the evaluation of administering therapeutics by intracerebral microinfusion as a method of achieving maximum intratumoral concentration while minimizing systemic exposure. and thereby significantly improving drug therapeutic index. Fourth, we are continuing to evaluate cytotoxic chemotherapeutics that have shown promising, preclinical efficacy in the extensive Duke panel of brain tumor cell lines and xenograft models.